Fluocinolone Acetonide is an anti-inflammatory corticosteroid successfully used for topical treatment of otic inflammation. It is known in combination with an antibacterial and an antiseptic for treatment of external or middle ear infections (cf. e.g. US 20090111780 A1).
Fluocinolone Acetonide (a 6,9-difluoro-16,17-acetonide corticosteroid) is classified as high to medium potency anti-inflammatory agent depending on the concentration and the vehicle used. The 9-F group increases glucocorticoid activity and prevents metabolic oxidation of the 11-OH group (cf. e.g. T. L. Lemke and D. A. Williams, “Foye's Principles of Medicinal Chemistry”, Wolters Kluwer 2007, 6th ed., p. 902).
Fluocinolone Acetonide is virtually insoluble in water. It is actually more insoluble than other corticosteroids (e.g. Dexamethasone or Hydrocortisone) that are also used for similar purposes. The acetonide (ketal) moiety at the 16,17-position of fluocinolone provides potency as topical anti-inflammatory agent as it enhances lipophilicity (ibid, p. 895), but consequently reduces solubility. In fact, otic drops containing Fluocinolone Acetonide are organic solutions (e.g. otic oil drops commercialized by Hill Dermaceuticals) or aqueous-organic suspensions (e.g. the aqueous suspension preparations described in EP 1312356 A1). Otic drops containing Fluocinolone Acetonide and Ciprofloxacin are on the market in the form of aqueous-organic composition containing preservatives and less than 75% of water (e.g. otic drops commercialized by Salvat in Spain for treatment of external otitis).
Examples of disorders that entail otic inflammation are eczematoid external otitis, keloids, granular myringitis, bullous myringitis or sudden deafness. Examples of disorders that entail otic inflammation accompanied by bacterial infection are diffuse external otitis (swimmers's ear), localized external otitis (forunculosis), traumatic tympanic membrane perforations, herpes zoster oticus (Ramsay Hunt syndrome), otitis media with effusión (OME, also called serous or secretory otitis media (SOM) or glue ear), otorrhea through tympanostomy tubes, acute otitis media with tympanostomy tubes (AOMT), acute otitis media (AOM) or chronic suppurative otitis media (CSOM).
In some cases, the presence in otic drops of solvents different from water and/or preservatives entails some adverse effects, such as allergic responses or irritation (cf. e.g. J. Coloe and M. J. Zirwas, “Allergens in corticosteroid vehicles”, Dermatitis 2008, vol. 19(1), pp. 38-42). Also, some concerns about the suitability of using preservatives such as parabens for topical application have been raised due to their potential toxicity (cf. e.g. P. D. Darbre and P. W. Harvey, “Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks”, J Appl Toxicol. 2008, vol. 28(5), pp. 561-578). Thus, it is highly desirable to provide improved pharmaceutical compositions with vehicles of higher water content for treatment of otic inflammation, especially in cases where it is accompanied by bacterial infection.